Browsing by Author "Djordjevic, Ana (26538582300)"

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients. © 2023 by the authors.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients. © 2023 by the authors.

Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study was to investigate whether visceral adipose tissue inflammation linked to abdominal obesity and dyslipidemia could lead to impaired insulin sensitivity in the animal model of polycystic ovary syndrome. Female Wistar rats were treated with nonaromatizable 5α-dihydrotestosterone pellets in order to induce reproductive and metabolic characteristics of polycystic ovary syndrome. Glucose, triglycerides, non-esterified fatty acids and insulin were determined in blood plasma. Visceral adipose tissue inflammation was evaluated by the nuclear factor kappa B intracellular distribution, macrophage migration inhibitory factor protein level, as well as TNFα, IL6 and IL1β mRNA levels. Insulin sensitivity was assessed by intraperitoneal glucose tolerance test and homeostasis model assessment index, and through analysis of insulin signaling pathway in the visceral adipose tissue. Dihydrotestosterone treatment led to increased body weight, abdominal obesity and elevated triglycerides and non-esterified fatty acids, which were accompanied by the activation of nuclear factor kappa B and increase in macrophage migration inhibitory factor, IL6 and IL1β levels in the visceral adipose tissue. In parallel, insulin sensitivity was affected in 5α-dihydrotestosterone-treated animals only at the systemic and not at the level of visceral adipose tissue. The results showed that abdominal obesity and dyslipidemia in the animal model of polycystic ovary syndrome were accompanied with low-grade inflammation in the visceral adipose tissue. However, these metabolic disturbances did not result in decreased tissue insulin sensitivity.

Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study was to investigate whether visceral adipose tissue inflammation linked to abdominal obesity and dyslipidemia could lead to impaired insulin sensitivity in the animal model of polycystic ovary syndrome. Female Wistar rats were treated with nonaromatizable 5α-dihydrotestosterone pellets in order to induce reproductive and metabolic characteristics of polycystic ovary syndrome. Glucose, triglycerides, non-esterified fatty acids and insulin were determined in blood plasma. Visceral adipose tissue inflammation was evaluated by the nuclear factor kappa B intracellular distribution, macrophage migration inhibitory factor protein level, as well as TNFα, IL6 and IL1β mRNA levels. Insulin sensitivity was assessed by intraperitoneal glucose tolerance test and homeostasis model assessment index, and through analysis of insulin signaling pathway in the visceral adipose tissue. Dihydrotestosterone treatment led to increased body weight, abdominal obesity and elevated triglycerides and non-esterified fatty acids, which were accompanied by the activation of nuclear factor kappa B and increase in macrophage migration inhibitory factor, IL6 and IL1β levels in the visceral adipose tissue. In parallel, insulin sensitivity was affected in 5α-dihydrotestosterone-treated animals only at the systemic and not at the level of visceral adipose tissue. The results showed that abdominal obesity and dyslipidemia in the animal model of polycystic ovary syndrome were accompanied with low-grade inflammation in the visceral adipose tissue. However, these metabolic disturbances did not result in decreased tissue insulin sensitivity.

Purpose: Polycystic ovary syndrome (PCOS) is a complex reproductive disorder often associated with obesity, insulin resistance, and dyslipidemia. Hormonal changes in PCOS may also include altered glucocorticoid signaling. Our aim was to examine whether alterations in hepatic glucocorticoid signaling are associated with disturbances of glucose and lipid metabolism in animal model of PCOS. Methods: Female rats, 3 weeks old, were subcutaneously implanted with 5α-dihydrotestosterone (DHT) or placebo pellets for 90 days to induce PCOS. Expression of 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) and A-ring reductases (5α and 5β), as well as intracellular distribution of glucocorticoid receptor (GR) and expression of its regulated genes were examined in the liver. Proteins of hepatic lipid and carbohydrate metabolism and markers of inflammation were also assessed. Results: DHT treatment induced increase in body and liver mass, as well as in triglycerides and free fatty acids levels in plasma. Elevation of 11βHSD1 and reduction of 5α-reductase expression was observed together with increased hepatic corticosterone concentration and nuclear GR activation. Induced expression of Krüppel-like factor 15 and decreased expression of genes for proinflammatory cytokines and de novo lipogenesis (DNL) were detected in the liver of DHT-treated rats, while DNL regulators and proinflammatory markers were not changed. However, increased mRNA levels of stearoyl-CoA desaturase and apolipoprotein B were observed in DHT animals. Conclusions: DHT treatment stimulated hepatic glucocorticoid prereceptor metabolism through increased corticosterone availability which is associated with enhanced GR activation. This does not affect gluconeogenesis and DNL, but could be linked to stimulated triglyceride synthesis and hypertriglyceridemia. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Purpose: Polycystic ovary syndrome (PCOS) is a complex reproductive disorder often associated with obesity, insulin resistance, and dyslipidemia. Hormonal changes in PCOS may also include altered glucocorticoid signaling. Our aim was to examine whether alterations in hepatic glucocorticoid signaling are associated with disturbances of glucose and lipid metabolism in animal model of PCOS. Methods: Female rats, 3 weeks old, were subcutaneously implanted with 5α-dihydrotestosterone (DHT) or placebo pellets for 90 days to induce PCOS. Expression of 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) and A-ring reductases (5α and 5β), as well as intracellular distribution of glucocorticoid receptor (GR) and expression of its regulated genes were examined in the liver. Proteins of hepatic lipid and carbohydrate metabolism and markers of inflammation were also assessed. Results: DHT treatment induced increase in body and liver mass, as well as in triglycerides and free fatty acids levels in plasma. Elevation of 11βHSD1 and reduction of 5α-reductase expression was observed together with increased hepatic corticosterone concentration and nuclear GR activation. Induced expression of Krüppel-like factor 15 and decreased expression of genes for proinflammatory cytokines and de novo lipogenesis (DNL) were detected in the liver of DHT-treated rats, while DNL regulators and proinflammatory markers were not changed. However, increased mRNA levels of stearoyl-CoA desaturase and apolipoprotein B were observed in DHT animals. Conclusions: DHT treatment stimulated hepatic glucocorticoid prereceptor metabolism through increased corticosterone availability which is associated with enhanced GR activation. This does not affect gluconeogenesis and DNL, but could be linked to stimulated triglyceride synthesis and hypertriglyceridemia. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is closely associated with chronic low-grade inflammation and insulin resistance. To clarify the contribution of prepubertal weight gain to the development of insulin resistance in PCOS, we investigated the effects of early postnatal overfeeding on inflammatory and energy-sensing pathways as well as on markers of insulin signaling in the liver of the PCOS rat model. Methods: Obesity induced by overfeeding was achieved by reducing litter size, while the PCOS-like condition was developed by treatment with 5α-dihydrotestosterone (DHT). Western blot and qPCR were used to analyze the expression of pro-inflammatory transcription factors and cytokines, as well as markers of the energy sensing and insulin signaling pathways. Results: The results showed that hepatic insulin sensitivity was impaired only in DHT-treated rats raised in small litters, as evidenced by increased phosphorylation of IRS1 on Ser307 and decreased expression of total IRS1. Postnatal overfeeding stimulated JNK1 activation independent of hyperandrogenemia; nevertheless, the synergistic effect of both factors triggered NLRP3 activation and increased IL1β expression in the small litter DHT-treated group. This pro-inflammatory state was accompanied by decreased activatory phosphorylation of AMPK and reduced levels of its protein targets. Conclusions: Overfeeding in the early postnatal period leads to a decrease in hepatic insulin sensitivity in the rat model of PCOS, which is associated with decreased activation of AMPK and stimulation of the hepatic NLRP3-IL1β signaling pathway. Accordingly, the inhibition of NLRP3 activation could provide a basis for the development of new therapeutic strategies for the treatment of insulin resistance in women with PCOS. Copyright © 2024 Veličković, Mićić, Teofilović, Milovanovic, Jovanović, Djordjevic, Macut and Vojnović Milutinović.